Title of Invention

PROCESS FOR THE PREPARATION OF N- [4- (3,4-DICHLORO PHENYL) -3, 4 - DIHYDRO -1 -(2H) - NAPHTHALENYLIDENE] METHANAMINE (SERTRALINE INTERMEDIATE)

Abstract The present invention is to provide a commercially feasible process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-{2H)-naphthalenylidene] -methanamine (Sertraline) by the reaction of 4-{3, 4-dichlorophenyl)-3, 4- dihydro-l- (2H)-naphthalenone with excess of aqueous monomethylamine without the requirement of anhydrous conditions, catalysts and pressure reactions.
Full Text

Field of the Invention:
The present invention relates to a novel process for the preparation of N- [4-(3,4-dichlorophenyl)-3,4-dihydro-l-{2H)-naphthalenylidene] methanamine by reacting 4-(3,4-dichlorophenyl)- 3,4 - dihydro- 1 - (2H)-naphthalenone with aq.monomethylainine in water miscible solvent (s).
Background of the Invention:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-{2H)-naphthalenylidene]-methanamine is a useful intermediate for the preparation of sertraline hydrochloride namely (+)-cis-(IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine,which has the structure as given below

Sertraline hydrochloride is used for the treatment of depression, obsessive-compulsive disorder and panic disorder. Sertraline was first disclosed in the European Patent EP 30081.
Various routes of synthesis have been used or suggested for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-{2H)-naphthalenylidene] methanamine.
U.S. Patent No. 4,536,518 equivalent to EP 30081 discloses a process for the preparation of sertraline hydrochloride, involving condensation of 4- (3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with mono methylamine and catalyzed by titanium tetrachloride yielding N -[4-(3,4-dichlorophenyl)- 3,4-dihydro-1-(2H)-naphthalenylidene] methanamine under anhydrous conditions.
U.S. Patent No. 4,855,500 discloses a process for the preparation of N-4- (3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]-methanamine in which

molecular sieves are employed to achieve the anhydrous condition for the reaction to promote the condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone and monomethylamine.
PCT Publication No, WO 99/36394 discloses a process in which the condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone with mono methylamine is performed in sub surface manner in an alcohol solvent under pressure up to 60 psi. This reaction is also carried out under anhydrous conditions.
U.S. Patent application 2003/013,768 discloses a process in which an amide solvent is employed and the imination reaction is carried out under anhydrous condition with positive pressure of inert gas, such as nitrogen or argon in presence of acid catalyst such as formic acid. This process requires an additional step involving the washing of the product with other solvent for removal of amide solvent, which also results in lowering of yield.
The prior art emphasizes the need for anhydrous conditions for the reaction of 4- (3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with monomethyl amine. Moreover the final product obtained is contaminated with catalyst / by-product of catalyst employed in the reaction. An additional step becomes is imperative in the prior art to separate the final product from the catalyst / by-product of the catalyst.
It is a longstanding need to provide an industrially viable cost-effective process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4~dihydro -1- {2H) -naphthalenylidene]-methanamine without the use of anhydrous conditions, molecular sieves, catalyst etc or need of additional purification step as taught in the prior art.
Sximmary of the invention:
The main object of the present invention is to provide a commercially feasible, eco-friendly process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]-methanamine obviating the need for anhydrous conditions, molecular sieves, catalyst etc or additional purification steps.

Another object of the present invention is to provide the process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene] -. methanamine in water, water miscible solvent(s)
Yet another object of the present invention is to provide the process for the preparation of N -[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene] -methanamine without any catalyst.
It has surprisingly been found that it is possible to react 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with excess of aqueous monomethylamine to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]-methanamine without the requirement of anhydrous conditions and / or catalysts as depicted in the scheme-I.

4-(3,4-dichlorophenyl)-3,4-dihydro N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-
-1- (2H) -naphthalenone (2H) -naphthalenylidene] -methanamine
Detailed description of the invention:
The process of the present invention comprises:
Reaction of 4-(3,4-dichlorophenyl) -3,4-dihydro-l- (2H)-naphthalenone
with aqueous monomethylamine at atmospheric pressure and ambient
temperature in presence of water, water miscible organic solvent(s)
Separation of product
Washing of wet cake with water /water miscible solvent(s) mixture and
water
- Drying of the product at 50-75 °C. The reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenone /its chiral isomers with excess of aqueous monomethylamine as represented in the above scheme is carried out at atmospheric pressure in any water miscible

solvent(s) such as: alcohols containing carbon atom Ci-Cg, acetone, 1,4-dioxane, tertrahydrofuran, ethylene glycocol dimethylether, digol,glycerol, acetonitrile, N,N-dimethylformamide and N-methyl-2-pyrrolidone.
The preferred solvents are 1,4-dioxane, tertrahydrofuran, acetonitrile, methanol, ethanol and isopropyl alcohol the most preferred solvent being 1,4-dioxane.
The water miscible solvent used in the reaction is in ratio of 1:1 to 1:10 (w/v) , preferably in the ratio 1:2 to 1:3 (w/v) with respect to 4 - (3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone employed in the reaction. The concentration of aqueous monomethylamine solution used in the reaction is -5-50 % (w/v), preferably 35-45 %( w/v).
The molar quantities of aqueous monomethylamine employed in the reaction is about 1-50 moles with respect to 4-(3, 4-dichlorophenyl)-3, 4-dihydro-l-(2H)-naphthalenone, preferably about 20 moles and most preferably about 10 moles.
The reaction is carried out in the temperature range of about 0°C tol50°C,
preferably at about 10°C to 60°C, and most preferably at about 25°C to 48°C. The reaction is continued under the conditions described above until such time as it is substantially complete. The reaction can reach to completion in 4 hours to 15 days, however it is completed preferably in 12-60 hours, most preferably 16-30 hours. After completion of reaction the resulting mass is
cooled to about 5°C to 20°C, and the product N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]methanamine / its chiral isomers is separated by filtration / centrifugation, washed with water / water-solvent mixture prior to drying.
As is evident from the above description, the reaction of 4-(3,4-dichlorophenyl) -3,4-dihydro-l- (2H)-naphthalenone with aq. monomethylamine is carried out without creating anhydrous conditions or use of catalysts as emphasized in the prior art. Further, as the reaction is carried out without any catalyst, product obtained is free from contamination of catalyst / by product of catalyst. Furthermore the removal of solvent and monomethylamine from the product is achieved by washing the wet cake with water / water-miscible solvent.

The resulting imine compound i.e., N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene] methanamine is used for the preparation of sertraline hydrochloride or (+)-cis-(IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.
The invention will be more clearly understood with reference to the following Examples.
Example-l: Preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l*(2H)-naphthalenylidene] methanamine:
400 ml of aqueous monomethylamine solution (35-40%w/v) is added to a mixture of 400 ml 1,4-dioxane and 200g 4-(3, 4-dichlorophenyl)-3,4-dihydro-l-{2H)-
naphthalenone at 25-30°C. The mixture is stirred at 4 0-4 5°C for 24-30 hrs.
After completion of reaction, the reaction mixture is cooled to 15°C and
filtered. The cake is washed with 100 ml (50% v/v) chilled aqueous 1,4-dioxane
followed by 100ml water. The wet cake is dried at 60-65°C for 10 hrs.
Yield: 200g (1.0 w/w)
Purity: > 94% ; Melting Range: 138-144°C.
Example-2: Preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H) naphthalenylidene] methanamine:
20g 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone is treated 40 ml of aqueous monomethylamine solution (35-40%w/v) at 25-35°C for 15 days and additional quantity of 220 ml aqueous monomethylamine solution (35-40%w/v) is added periodically to the reaction mixture during the course of reaction. After completion of reaction, the reaction mixture is cooled to 15°C and filtered. The cake is washed with 20ml water. The wet cake is dried at 60-65°C for 10 hrs. Yield: 19.4g (0.97 w/w)
Purity: > 93%; Melting Range: 138-144°C.
Excaaple-3; The reaction is carried out in similar conditions using tetrahydrofuran as solvent as described in example-l. Yield = 0.84 (w/w); Purity: 98%

Excunple-4: The reaction is carried out in similar conditions using ethylene glycocol dimethyl ether as solvent as described in example-1. Yield = 0.80 (w/w); Purity: 98%
Example-5: The reaction is carried out in similar conditions using digol as solvent as described in example-1. Yield = 0.90 (w/w); Purity: 93%
Example-6: The reaction is carried out in similar conditions using glycerol as solvent as described in example-1. Yield = 0.95 (w/w); Purity: 91%
Example-7: The reaction is carried out in similar conditions using acetonitrile as solvent as described in example-1. Yield = 0.9 (w/w); Purity: 94.5%
Example-8: The reaction is carried out in similar conditions using N,N-dimethylformamide as solvent as described in example-1. Yield = 0,94 (w/w); Purity: 95.5%
Excuaple-9: The reaction is carried out in similar conditions using ethanol as solvent as described in example-1. Yield - 0,94 (w/w); Purity: 92%
Example-10: The reaction is carried out in similar conditions using N-methyl-2-pyrrolidone as solvent as described in example-1. Yield = 0.8 (w/w); Purity: 97%




We claim:
1. A novel process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-
dihydro-1-(2H)-naphthalenylidene] methanamine comprising:
Reacting aq. monomethylamine with 4-(3, 4-dichlorophenyl) -3, 4-dihydro-1-(2H)-naphthalenone at atmospheric pressure and ambient temperature in presence of water, water miscible organic solvent (s). Separating the product
Washing the wet cake with water/water miscible solvent(s) mixture and water.
Drying the product at about 50°C -75*^0.
2. A process as claimed in claim 1, N- [4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]methanamine is recemic mixture or its stereo isomers.
3. A process as claimed in claim 1, wherein the concentration of aqueous monomethylamine used in the reaction is ^ 5-50% (w/v)^ preferably 35-45%
(w/v).
4. A process as claimed in claim 1, wherein the water miscible organic
solvent (s) are selected from alcohols containing carbon atoms Ci-Cg, acetone,
1,4-dioxane, tertrahydrofuran, ethylene glycocol dimethyl ether, digol,
glycerol, acetonitrile, N,N-dimethylformamide, and N~methyl-2-pyrrolidone.
5. A process as claimed in claims 1 and 4, wherein the preferred water miscible organic solvent(s) is selected from 1,4-dioxane, tertrahydrofuran, acetonitrile, methanol, ethanol and Isopropyl alcohol.
6. A process as claimed in claim 1, 4 and 5, wherein the most preferred water miscible organic solvent is 1,4-dioxane.
7. A process of claim 1, wherein the molar ratio of aqueous monomethylamine for the reaction is about 1:50 w.r.t. 4-(3, 4-dichlorophenyl)-3, 4-dihydro-l-(2H)-naphthalenone, preferably about 1:20 and most preferably about 1:10.

8. A process of claim 1, wherein the water miscible solvent (s) used in the
reaction is about 1:10 w.r.t. 4-(3, 4-dichlorophenyl)-3, 4-dihydro-l-(2H)-
naphthalenone, preferably 1:2 to 1:3.
9, A process as claimed in claim 1, wherein the temperature for the reaction is
0°C to 48°C, preferably IQ°C to 48^C and most preferably at 25'C to 48°C.


Documents:

915-che-2003-abstract.pdf

915-che-2003-claims duplicate.pdf

915-che-2003-claims original.pdf

915-che-2003-correspondence others.pdf

915-che-2003-correspondence po.pdf

915-che-2003-description complete duplicate.pdf

915-che-2003-description complete original.pdf

915-che-2003-form 1.pdf

915-che-2003-form 19.pdf

915-che-2003-form 3.pdf


Patent Number 204276
Indian Patent Application Number 915/CHE/2003
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 13-Feb-2007
Date of Filing 10-Nov-2003
Name of Patentee M/S. MATRIX LABORATORIES LTD
Applicant Address 1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD, SECUNDERABAD, 500 003,
Inventors:
# Inventor's Name Inventor's Address
1 DR. BANDARI MOHAN FLAT NO.202, H. NO 8-3-169/7 DHANANJAYA ENCLAVE, ST NO.5 VENGALARAO NAGAR HYDERABAD-500 038
2 DR. MADHURESH KUMAR SETHI G-3,SAI BRINDAVANAM APARTMANT RAMAKRISHANA ST, VIVEKANANDA NAGAR COLONY, KUKATPALLY HYDERABAD-500 072
3 DR. GINJUPALLI SAI PRASANNA BHAGYA LAKSHMI 109-SWASTIC RESIDENCY BAGH AMEER, KUKATPALLY HYDERBAD 500 072
PCT International Classification Number C07C 119/14
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA